spatial learning cells that code for space synaptic plasticity in the hippocampus

spatial learning cells that code for space synaptic plasticity in the hippocampus experiments that are knockouts summary

PART 4: BEHAVIORAL PLASTICITY#25: SPATIAL NAVIGATION IN RATS II

spatial learning cells that code for space synaptic plasticity in the hippocampus experiments that are knockouts summary

PART 4: BEHAVIORAL PLASTICITY#26: SPATIAL NAVIGATION IN RATS II

CODING SPACE – HIPPOCAMPAL PLACE CELLS

place cells encode more than simple space T-maze, trained (fruit loops) to alternate L & R turns subset of place cells showed interesting pattern e.g., activity (sector 3) anticipating right turns only

suggests hippocampal network represents episodic memories, cells are small segments of an episode link of cells with overlapping episodes memories

spatial dreaming large # space cells

only ~ 15% active in any 1 environ. some silent in one environ., active in others time- & labor-intensive to get larger picture

device to measure 150 cells at once population or ensemble code

code predicts rat behavior in maze many environments & codes overlapping, not interfering

used to study plasticity...


spatial dreaming plasticity

strengthening of code learning accompanied by reduced inhibitory activity

does code relate to consolidated (permanent) memory trained rats in spatial task measured code during

training sleeping before training sleeping after training

dreaming replay of events memory consolidation


CODING SPACE – HEAD DIRECTION CELLS

navigation requires knowledge of place direction... another class of cells...

in another structure... postsubiculum cells fire ~ head position

basic features of head direction cells retain direction preference in novel environments ~ 90° arc around preferred direction populations of cells with different preferences not ~ rat position in environment ~ independent of rat’s own behavior


common features of head direction cells & place cells influenced by salient external cues direction cells also fire after cues (light) removed capable of deduced reckoning using ideothetic cues informed by vestibular and visual input direction cells do not remap in a novel environments


navigation involves computation by the brain temporal process (~ video vs photograph) memory of past events prediction of future events processed by sub-populations of head direction cells 2 areas measured in behaving rats

postsubicular cortex (PSC) anterodorsal nucleus (ADN) of thalamus


navigation involves computation by the brain analyzed firing pattern relative to

momentary head direction both cell types have preferred direction


navigation involves computation by the brain analyzed firing pattern relative to

angular velocity PSC retain preference ADN shift preference future position


navigation involves computation by the brain ADN shift preference predict future position e.g., if a cell (of many) prefers 180° it may fire @

160° when 180° 200° when 180° 180° when @ 180° (future = present)


why bother with all of this?... in theory... deductive reckoning circuit direction cells work by integrating internal cues ADN cells combine information about

current head direction head movement (turning)

proposed that PSC & ADN cells... constitute a looping circuit, compute direction by integrating motion/time but... how is “time” measured?


SYNATPTIC PLASTICITY IN THE HIPPOCAMPUS

how do place cells and head directions cells learn to change their preferences? maintain their preferences over time?

clues from electrophysiology experiments... brief, high-frequency stimulation of trisynaptic circuit...

all 3 pathways

increased excitatory postsynaptic potentials (EPSPs) in postsynaptic hippocampal neurons

synaptic facilitation increase lasts for hours 3 sites, 3 patterns, CA1 measured in brain

“slices”

phenomenon called long-term potentiation (LTP) a very big deal in mammalian cell.-phys. of learning but... difficult to demonstrate relevance for behavior

SYNATPTIC PLASTICITY IN THE HIPPOCAMPUS

3 properties of LTP in hippocampus CA1 neurons cooperativity: a minimum # of CA1 fibers must be

activated together (1 weak, 2 bottom strong)

SYNATPTIC PLASTICITY – LTP IN CA1

3 properties of LTP in hippocampus CA1 neurons associativity: a weak tetanus paired with a strong

will gain - by association - value of strong measured in response after “training” (3 top) features ~ behavior, associative learning



3 properties of LTP in hippocampus CA1 neurons specificity: LTP can be restricted to single activated

pathway (2 bottom), others unchanged (2 top) localized to

regions of hippocampus inputs regions on single cells (2)

SYNATPTIC PLASTICITY – LTP IN POSTSYNAPTIC CELLS

CA1 pyramidal neurons LTP in CA1 is dependent on pyramidal neurons (PNs)

inhibition of PN activity blocks LTP in CA1 hyperpolarize PN membrane blocks LTP in CA1 blocked inhibition of PN facilitates LTP in CA1 depolarize PN membrane

facilitates LTP in CA1 during weak tetanus not on its own (i.e., effect is associative)

the postsynaptic cell must be depolarized for LTP to occur in the presynaptic cell

SYNATPTIC PLASTICITY – LTP & NMDA RECEPTORS

glutamate (GLU), main excitatory transmitter (brain) N-methyl-D-aspartate (NMDA) 1 (of many) receptors LTP requires depolarization to open NMDA channel

doubly gated channel, by.. GLU (receptor) & voltage (sensor)

evidence for NMDA involvement in LTP NMDA blockers, e.g. aminophosphnovalerate (APV)

blocks NMDA activity blocks LTP

cooperativity: GLU from weak input depolarize postsynaptic cell strong input depolarizes postsynaptic cell

associativity: GLU from strong input depolarizes postsynaptic cell weak input (paired) opens NMDA channels*


evidence for NMDA involvement in LTP Hebb’s Rule: synapses are strengthened if a presynaptic cell repeatedly participates in driving spikes in a postsynaptic cell GLU & NMDA receptor satisfies the rule have coincident activity of cells

presynaptic release of GLU receptors postsynaptic depolarization by non-NMDA receptors


Ca++ influx into the postsynaptic cell is required for LTP block calcium (buffer)

blocks LTP calcium influx through NMDA receptor/channel


evidence for NMDA involvement in LTP specificity: dendritic spines

NMDA receptors on dendritic spine heads Ca++ entry restricted by necks anatomical subdivisions


Ca++ influx into the postsynaptic cell is required for LTP Ca++ LTP mediated by 2nd messenger signaling

Ca++/calmodulin kinase (CaMKII) protein kinase C (PKC)


2 types of LTP described in CA1 neurons early-phase LTP (E-LTP)

1 3 h cAMP & protein synthesis-independent

late-phase LTP (L-LTP) 10 h + cAMP & protein synthesis-dependent

LTP in rats ~ long-term synaptic facilitation in Aplysia long-term memory in Drosophila


SYNATPTIC PLASTICITY – LTP & SPATIAL LEARNING

does LTP have anything to do with learning?... difficult spatial learning & memory in the water maze

block LTP with AP5 block memory ask the 3 Qs...

correlation? necessity? sufficiency?

does LTP have anything to do with learning?... difficult spatial learning & memory in the circular platform maze

aging LTP ~ aging memory ask the 3 Qs...


SYNATPTIC PLASTICITY – LTP & SPATIAL LEARNING

EXPERIMENTS THAT ARE KNOCKOUTS (MOUSE)

genetic engineering - e.g. already with Drosophila transgenic “knockouts” (also “knockins”) single gene manipulations LTP & spatial learning fyn gene knockout are tyrosine kinase– and... knockouts of CaMKII–

LTP in CA1 cells spatial learning ask the 3 Qs...


CaMKII knockouts - enzyme cannot be Ca++ modulated LTP impaired (in “functional” range) place cells

fewer specificity focus stable

platform maze spatial learning

ask the 3 Qs...


NMDA receptor knockouts LTP severely impaired place cells (multi-elect.)

specificity coordinated firing

NMDA-receptor-mediated synaptic plasticity required for proper representation of space in CA1 region of hippocampus


NMDA receptor knockouts water maze

spatial learning

ask the 3 Qs... arguments more compelling with each experiment spatial & temporal targeting of knockout, correlation of lesion, LTP, behavior remains


SUMMARY spatial navigation uses 2 types of cues

external (landmarks) internal (ideothetic) deductive reckoning (memory)

spatial navigation studied in rats using radial arm maze T-maze water maze circular platform maze

tasks are designated as spatial (using distal cues) cued (or non-spatial, using proximal cues)

lesion studies, hippocampus for spatial learning if lesions precede learning

working & reference memory tasks are impaired cued tasks are not impaired

if learning precedes lesions time between events important usually older memories are less affected

SUMMARY

two classes of neurons encode space place cells, CA1 hippocampus

firing field stability ~ weeks, memory influenced by

external cues (landmarks) internal cues (vestibular, visual ~ motion)

field in dark ~ active can be event-related, predictive (e.g., turning) work together ensemble code replay in sleep... consolidation?... dreaming?

SUMMARY

two classes of neurons encode space head direction cells, CA1 hippocampus

fire ~ head direction similarly influenced by

external cues (landmarks) internal cues (vestibular, visual ~ motion)

2 types of cells PSC cells encode current direction ADN cells encode future direction

SUMMARY

LTP is a prominent form of hippocampal synaptic plasticity, with the following properties:

cooperativity associativity specificity

LTP in CA1 neurons ~ NMDA receptor, 2 requirements: depolarization of the postsynaptic cell binding of glutamate with the NMDA receptor allows channel opening, Na+ & Ca++ influx Ca++ influx is required for induction of LTP

SUMMARY

NMDA receptor mechanism for Hebb’s Rule

Evidence that LTP underlies (or is involved with) mechanisms for learning

drugs blocking LTP also block spatial learning aging affects LTP and spatial learning mice knockouts for “LTP genes” show deficits in

LTP place cell properties spatial learning

SUMMARY

spatial learning cells that code for space synaptic plasticity in the hippocampus

Documents

Transcript of spatial learning cells that code for space synaptic plasticity in the hippocampus